PROJECT SUMMARY ? LYMPHOMA & LEUKEMIA PROGRAM The goal of the Lymphoma and Leukemia (LL) Program is to gain a better understanding of the biology underlying lymphoid and myeloid neoplasms and to apply this knowledge to improve the diagnosis and treatment of these disorders. In working toward this goal, this broad research program encompasses major aims of disease pathogenesis, clinical pathological relationships, the use of biomarkers in patient stratification, novel therapeutics, and clinical trials. Program members have emphasized translational research to the clinic in diagnostics and novel therapeutics, and from the clinic to the laboratory in correlative studies on tissues matched with clinical events. The laboratory-based projects are focused on the characterization of leukemia stem cells; elucidation of signaling pathways in individual tumor cells; determination of mechanisms of lymphomagenesis with specific attention to the MYC oncogene, and analysis of the role of the immune system in specific relation to lymphomas and leukemias. Novel diagnostics have been developed, including the discovery of founder genetic mutations and novel tests for monitoring tumor responses using cell-free DNA. The LL Program has developed new ways of enhancing the therapeutic activity of monoclonal antibodies by stimulating NK killer cells (anti-CD137), novel drug- antibody conjugates (Brentuximab Vedotin), and a new method of therapeutic vaccination (in situ vaccination with TLR9 ligands and immune checkpoint antibodies). Program members have also played major roles in the development of novel targeted therapies (BTK inhibitor, Ibrutinib, and the PI3 kinase delta inhibitor, Idealisib). Studies from the program have been influential in changing medical practice worldwide. Future plans include combining targeted small molecules with immunotherapies in the hope of replacing current cytotoxic chemotherapy regimens with safer, more effective therapies. Co-led by Ronald Levy, MD and Ravindra Majeti, MD, PhD the 24 LL Program members represent 11 departments within the School of Medicine and the School of Engineering. Peer-reviewed funding is represented by a total of $6.7M in total annual costs of which $4.2M is from the NCI, $0.9M from other NIH sources, and $1.7M from other peer-reviewed support mechanisms. Since 2009, program investigators have published over 375 manuscripts, of which 28% are intra-programmatic, 32% inter-programmatic, and numerous manuscripts with external collaborators. The SCI will continue to be invaluable in the seeding of innovative projects and assisting with the translation of basic science findings of this program into new clinical approaches for the diagnosis and treatment of patients with Lymphoma and Leukemia.